The University of Southampton
University of Southampton Institutional Repository

MicroRNA-31 targets thymic stromal lymphopoietin in mucosal infiltrated CD4+ T cells: a role in achieving mucosal healing in ulcerative colitis?

MicroRNA-31 targets thymic stromal lymphopoietin in mucosal infiltrated CD4+ T cells: a role in achieving mucosal healing in ulcerative colitis?
MicroRNA-31 targets thymic stromal lymphopoietin in mucosal infiltrated CD4+ T cells: a role in achieving mucosal healing in ulcerative colitis?
Background:

Ulcerative colitis (UC) is characterized by disruption of the mucosal intestinal barrier. MicroRNAs, single-stranded noncoding RNAs of approximately 22nt, are dysregulated in UC. MicroRNAs targeting thymic stromal lymphopoietin (TSLP), a cytokine involved in T-cell maturation and polarization, may be involved in regulating UC inflammation and mucosal healing.

Methods:

Biopsy samples from non-UC (n = 38), inactive UC (n = 18), and active UC (n = 23) patients were analyzed for mRNA (real-time quantitative polymerase chain reaction) or TSLP protein expression (enzyme-linked immunosorbent assay). Flow cytometry was used to isolate CD4+ T cells from biopsies. The functional mechanism was shown using luciferase assays and antago-miR transfections. The TSLP/miR-31 association was analyzed on 196 subjects from a previous clinical trial that tested the anti-IL-13 drug tralokinumab, whereas mucosal healing effects were studied on a subset of patients (n = 13) from this trial.

Results:

We found that TSLP is reduced at both mRNA and protein levels in inflamed UC patients when compared with healthy subjects, in both whole biopsies and biopsy-isolated CD4+ CD25+ T cells. The expression of miR-31, predicted to target TSLP, inversely co-related to the levels of TSLP mRNA in T cells. Blocking miR-31 in vitro in T cells increased both TSLP mRNA expression and protein secretion. Luciferase assays showed that miR-31 directly targeted TSLP mRNA, suggesting a direct mechanistic link. We also found that TSLP is increased in patients who achieve mucosal healing, comparing biopsies before and after treatment from the tralokinumab trial.

Conclusions:

Our data suggest a role for TSLP in promoting mucosal healing and regulating inflammation in UC, whereas miR-31 can directly block this effect.
2377–2385
Whiteoak, Simon R.
e733e00f-0927-4bed-80a3-eb8d4b06945c
Claridge, Andrew
2f9c856c-488f-4de9-9b5b-85b591f9d66c
Balendran, Clare
0b9d5d4f-71a6-4cd9-89a1-b174618192a8
Harris, Richard J.
8cc2fa3d-aab1-4fb4-b0b8-ad516cf5a08b
Gwiggner, Markus
af72b597-1ead-4155-a25c-0835f7e560c2
Bondanese, Victor P.
3a4cee7f-961a-43af-b011-12170923984b
Erlandsson, Fredrik
d8903cc5-fb59-4f19-af2c-e3e698f86297
Hansen, Mark Berner
99e90097-1ed6-4335-960a-a6ba8c55fdea
Cummings, J.R. Fraser
89e8e80c-b6e8-4387-a63c-3796b5ad7e14
Sanchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d
Whiteoak, Simon R.
e733e00f-0927-4bed-80a3-eb8d4b06945c
Claridge, Andrew
2f9c856c-488f-4de9-9b5b-85b591f9d66c
Balendran, Clare
0b9d5d4f-71a6-4cd9-89a1-b174618192a8
Harris, Richard J.
8cc2fa3d-aab1-4fb4-b0b8-ad516cf5a08b
Gwiggner, Markus
af72b597-1ead-4155-a25c-0835f7e560c2
Bondanese, Victor P.
3a4cee7f-961a-43af-b011-12170923984b
Erlandsson, Fredrik
d8903cc5-fb59-4f19-af2c-e3e698f86297
Hansen, Mark Berner
99e90097-1ed6-4335-960a-a6ba8c55fdea
Cummings, J.R. Fraser
89e8e80c-b6e8-4387-a63c-3796b5ad7e14
Sanchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d

Whiteoak, Simon R., Claridge, Andrew, Balendran, Clare, Harris, Richard J., Gwiggner, Markus, Bondanese, Victor P., Erlandsson, Fredrik, Hansen, Mark Berner, Cummings, J.R. Fraser and Sanchez-Elsner, Tilman (2018) MicroRNA-31 targets thymic stromal lymphopoietin in mucosal infiltrated CD4+ T cells: a role in achieving mucosal healing in ulcerative colitis? Inflammatory Bowel Diseases, 24 (11), 2377–2385. (doi:10.1093/ibd/izy213).

Record type: Article

Abstract

Background:

Ulcerative colitis (UC) is characterized by disruption of the mucosal intestinal barrier. MicroRNAs, single-stranded noncoding RNAs of approximately 22nt, are dysregulated in UC. MicroRNAs targeting thymic stromal lymphopoietin (TSLP), a cytokine involved in T-cell maturation and polarization, may be involved in regulating UC inflammation and mucosal healing.

Methods:

Biopsy samples from non-UC (n = 38), inactive UC (n = 18), and active UC (n = 23) patients were analyzed for mRNA (real-time quantitative polymerase chain reaction) or TSLP protein expression (enzyme-linked immunosorbent assay). Flow cytometry was used to isolate CD4+ T cells from biopsies. The functional mechanism was shown using luciferase assays and antago-miR transfections. The TSLP/miR-31 association was analyzed on 196 subjects from a previous clinical trial that tested the anti-IL-13 drug tralokinumab, whereas mucosal healing effects were studied on a subset of patients (n = 13) from this trial.

Results:

We found that TSLP is reduced at both mRNA and protein levels in inflamed UC patients when compared with healthy subjects, in both whole biopsies and biopsy-isolated CD4+ CD25+ T cells. The expression of miR-31, predicted to target TSLP, inversely co-related to the levels of TSLP mRNA in T cells. Blocking miR-31 in vitro in T cells increased both TSLP mRNA expression and protein secretion. Luciferase assays showed that miR-31 directly targeted TSLP mRNA, suggesting a direct mechanistic link. We also found that TSLP is increased in patients who achieve mucosal healing, comparing biopsies before and after treatment from the tralokinumab trial.

Conclusions:

Our data suggest a role for TSLP in promoting mucosal healing and regulating inflammation in UC, whereas miR-31 can directly block this effect.

Text
Accepted_manuscript_Whiteoak_Claridge_et_al_2018 - Accepted Manuscript
Download (108kB)
Text
Figures Whiteoak Claridge et al 2018
Download (586kB)

More information

Accepted/In Press date: 17 May 2018
e-pub ahead of print date: 8 June 2018

Identifiers

Local EPrints ID: 421450
URI: https://eprints.soton.ac.uk/id/eprint/421450
PURE UUID: 79b18030-8dea-4fa4-b564-d8d2feb26be9

Catalogue record

Date deposited: 12 Jun 2018 16:30
Last modified: 15 Aug 2019 04:11

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×